Niess Jan Hendrik, Hruz Petr, Kaymak Tanay (2018), The Interleukin-20 Cytokines in Intestinal Diseases, in Frontiers in Immunology
, 9, 1-9.
Raduolovic Katarina, Mak’Anyengo Rachel, Kaya Berna, Steinert Anna, Niess Jan Hendrik (2018), Injections of Lipopolysaccharide into Mice to Mimic Entrance of Microbial-derived Products After Intestinal Barrier Breach, in Journal of Visualized Experiments
, (135), 135.
Steinert Anna, Linas Ioannis, Kaya Berna, Ibrahim Mohamed, Schlitzer Andreas, Hruz Petr, Radulovic Katarina, Terracciano Luigi, Macpherson Andrew J, Niess Jan Hendrik (2017), The Stimulation of Macrophages with TLR Ligands Supports Increased IL-19 Expression in Inflammatory Bowel Disease Patients and in Colitis Models., in The Journal of Immunology
, 199(7), 2570-2584.
Piñero Paula, Juanola Oriol, Gutiérrez Ana, Zapater Pedro, Giménez Paula, Steinert Anna, Sempere Laura, González-Navajas José M., Niess Jan H., Francés Rubén (2017), IL26 modulates cytokine response and anti-TNF consumption in Crohn's disease patients with bacterial DNA, in J Mol Med
, 95(11), 1227-1236.
Rossini Valerio Radulovic Katarina Riedel Christian U. Niess Jan Hendrik (2016), Development of an Antigen-driven Colitis Model to Study Presentation of Antigens by Antigen Presenting Cells to T Cells., in J Vis Exp
, (115), e54421.
Steinert Anna Radulovic Katarina Niess. Jan J (2016), Gastro-intestinal tract: The leading role of mucosal immunity., in Swiss Med Wkly
, 146, w14293.
BACKGROUNDAlthough several subsets of mononuclear cells have been described in the lamina propria of the small and large intestine, mononuclear phagocytes have remained a rather undefined cell population. The development and analysis of fluorescent reporter mouse lines has led to the identification of CX3CR1+ mononuclear phagocytes in the intestine, which sample luminal microbes by extending processes into the intestinal lumen (Science 2005;307, 254). The characterization of CX3CR1+ mononuclear phagocytes has revealed that CX3CR1+ phagocytes are a heterogeneous cell population (J Immunol 2010; 180, 559), that can be distinguished in mononuclear phagocytes with high CX3CR1 or low CX3CR1 expression. Mononuclear phagocytes with high CX3CR1 expression express F4/80 and the tissue macrophage marker CD68 indicating a macrophage-like phenotype, produce IL-10, expand regulatory T cells in oral tolerance models and suppress T cells during transfer colitis. Mononuclear phagocytes with low CX3CR1 expression induce the differentiation of IFN-gamma secreting Th1 and IL-17A producing Th17 cells. Published work and our own results have indicated that macrophages produce the IL-10 type cytokine IL-19 and that the absence of IL-19 signalling in IL-20R2-/- animals is associated with accelerated colitis indicating that the IL-10 type cytokine IL-19 plays a role in the regulation of intestinal inflammation. OBJECTIVESIn this grant we will address if mononuclear phagocytes with high and low CX3CR1 expression differentially express IL-19 and mononuclear phagocyte-derived IL-19 suppresses intestinal inflammation. 1. The mononuclear phagocyte that produces IL-19 will be defined. 2. The role of phagocyte-derived IL-19 will be elucidated in innate colitis. 3. The suppression of T cell induced colitis by phagocyte derived IL-19 will be determined.METHODSTo identify IL-19+ phagocytes in the intestinal lamina propria we have generated IL-19TdTomato transgenic mice, in which the IL-19 promoter drives the expression of the red fluorescent protein TdTomato. After the identification of the cell that produces IL-19 we determine the role of phagocyte derived IL-19 in regulating intestinal inflammation with CD40 induced (innate) and T cell driven colitis models.SIGNIFICANCE The CX3CR1+ phagocyte - IL-19 system is critical for the maintenance of intestinal homeostasis, but poorly understood. In this grant the mononuclear cell that produces the IL-10 type cytokine IL-19 will be identified with help of novel mouse models, in which the IL-19 promoter drives the expression of the red fluorescent protein TdTomato and the importance of phagocyte-derived IL-19 for innate or T cell-driven colitis determined. The production of IL-19 by mononuclear cells after recognition of intestinal microbes could elucidate principles by which the mucosal immune system achieves the co-existence between the intestinal microflora and the host. An improved understanding of the CX3CR1+ phagocyte - IL-19 system has implications for our knowledge on the development of inflammatory bowel disease.